Macrophage/microglia cells are the principal targets for human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS). Prototype HIV-1 isolates from the CNS are macrophage (M)-tropic, non-syncytia-inducing (NSI), and use CCR5 for entry (R5 strains), but whether syncytia-inducing (SI) CXCR4-using X4 strains might play a role in macrophage/microglia infection and neuronal injury is unknown. To explore the range of features among HIV-1 primary isolates from the CNS, the authors analyzed an HIV-1 strain (TYBE) from cerebrospinal fluid of an individual with acquired immunodeficiency syndrome (AIDS) that was unusual because it was SI. Like other CNS isolates, HIV-1/TYBE replicated to high level in primary human macrophages, but, in contrast to CNS prototypes, TYBE used CXCR4 exclusively to infect macrophages. A functional TYBE env clone confirmed the X4 phenotype and displayed a highly charged V3 sequence typical of X4 strains. Supernatant from TYBE-infected primary human macrophages induced apoptosis of neurons. Thus, TYBE represents a novel type of CNS-derived HIV-1 isolate that is CXCR4-restricted yet replicates efficiently in macrophages and induce neuronal injury. These results demonstrate that HIV-1 variants in the CNS may possess a broader range of biological characteristics than generally appreciated, raise the possibility that X4 strains may participate in AIDS neuropathogenesis, and provide a prototype clade B HIV-1 strain that replicates efficiently in primary macrophages through the exclusive use of CXCR4 as a coreceptor.
To investigate the mechanism underlying one aspect of the cellular tropism of human immunodeficiency virus type 1 (HIV-1), we used a macrophage-tropic isolate, 89.6, and screened its ability to infect a number of continuous cell lines. HIV-1(89.6) was able to replicate robustly in a T-cell/B-cell hybrid line, CEMx174, while it replicated modestly or not at all in either of its parents, one of which is the CD4-positive line CEM.3. Analysis by transfection of a molecular clone, a virus uptake assay, and polymerase chain reaction all provided strong evidence that the block to HIV-1(89.6) replication in the CEM.3 line lies at the level of cellular entry. These results were complemented by preparing a CD4-expressing derivative of the B-cell parent, 721.174, and demonstrating that it is permissive for productive HIV-1(89.6) replication. Given these experimental findings, we speculate that there exist cellular accessory factors which facilitate virus entry and infection in CD4-positive cells. Furthermore, these cellular accessory factors may be quite virus strain specific, since not all macrophage-tropic strains of HIV-1 were able to replicate in the CEMx174 hybrid cell line. This experimental model provides a system for the identification of one or more of these putative cellular accessory factors.
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